Process for producing 2,6-diamino -1,4- dihydro-3,5-pyridine-dicarboxylates and derivatives thereof

ABSTRACT

2,6-Diamino-1,4-dihydropyridines bearing carbonyl functions in the 3- and 5-positions and being substituted in the 4-position by lower alkyl, phenyl, substituted phenyl or a heterocyclic group are antihypertensive agents and coronary vessel dilators. The compounds, of which 2,6-diamino-4-(3-nitrophenyl)-1,4dihydropyridine-3,5-dicarboxylic acid 3,5-diethyl ester is a representative embodiment, are prepared through condensation of an amidine with either an aldehyde or an ylidenecyanoacetoacetic acid ester.

United States Patent Meyer et a1.

PROCESS FOR PRODUCING 2,6-DIAMINO -1,4-

DIHYDRO-3,5-PYRIDINE- DICARBOXYLATES AND DERIVATIVES THEREOF Inventors: Horst Meyer; Friedrich Bossert,

both of Wuppertal-Elberfeld; Wulf Vater, Opladen; Kurt Stoepel, Wuppertal-Vohwinkel, all of Germany Assignee: Bayer Aktiengesellschaft, Germany Filed: Mar. 27, 1974 Appl. No.: 454,997

Foreign Application Priority Data Mar. 6, 1972 Germany 2210687 U.S. Cl 260/256.4 C; 260/256.4 R; 260/287 R; 260/294.8 D; 260/294.8 F; 260/2948 G; 260/295.5 R; 260/295.5 B

Int. Cl. C07D 51/36; CO7D 31/36 Field of Search 260/294.9, 294.8 G, 294.8 F, 260/295.5 R, 295.5 B, 294.8 D, 287 R, 256.4 C, 256.4 R

. r. Primary ExamznerAlan L. Rotman [57] ABSTRACT 2,6-Diamino-1,4-dihydropyridines bearing carbonyl functions in the 3- and 5-positions and being substituted in the 4position by lower alkyl, phenyl, substituted phenyl or a heterocyclic group are antihypertensive agents and coronary vessel dilators. The compounds, of which 2,6-diamino-4-(3-nitropheny1)-1,4- dihydropyridine-3,5-dicarboxylic acid 3,5diethyl ester is a representative embodiment. are prepared through condensation of an amidine with either an aldehyde or an ylidenecyanoacetoacetic acid ester.

33 Claims, No Drawings PROCESS FOR PRODUCING 2,6-DIAMI NO-1,4- DIHYDRO-3,5-PYRIDINE-DICARBOXYLATES AND DERIVATIVES THEREOF DETAILED DESCRIPTION This is a division of application Ser. No. 336,483 filed Feb. 28, 1973 now US. Pat. No. 8,355,231.

The present invention pertains to 2,6-diamino-l,4- dihydropyridine derivatives. to process for their production and use and to pharmaceutical compositions containing such compounds and useful as antihypertensive agents and coronary vessel dilators.

In particular, the present invention pertains to compounds of the formula:

wherein R is hydrogen; lower alkyl; lower alkenyl; lower alkynyl, phenyl; substituted phenyl in which the substituents are one to three members selected from the group consisting of lower alkyl, lower alkoxy, halogeno. nitro, cyano, trifluoromethyl, azido, carbo(lower alkoxy), lower alkylsulfonyl, lower alkylsulfinyl, lower alkylthio or phenyl; naphthyl; or a heterocyclic ring selected as, for example, cthynyl, Z-propynyl, 4-pcntynyl. and the like.

The term lower alkoxy denotes a straight or branched hydrocarbon chain bound to the remainder of the molecule through an ethereal oxygen atom as, for example. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy and hexoxy.

The term lower alkylthio denotes a branched or straight hydrocarbon chain bound to the remainder of the molecule through a divalent sulfur as, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, and the like.

The term halogen denotes the substituents fluro, chloro, bromo and iodo.

As indicated, the present invention also pertains to the physiologically acceptable non-toxic acid addition salts of these basic compounds. Such salts include those derived from organic and inorganic acids such as, without limitation, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methane sulphonic acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, embonic acid, enanthic acid, and the like.

According to the present invention, the foregoing compounds are prepared by reacting an amidine of the formula:

wherein R is as herein defined, with either (a) an aldehyde of the formula RCHO wherein R is as herein defined, or (b) with an ylidenecyanoacetic acid derivative of the formula:

I -CN of an alkali metal alkoxide such as sodium methoxide. The condensations proceed smoothly in good yields a a R 0c cor. R1 o 00R R1 0c CR2 a a l l I H l 2N N/ N32 H2 N NR2 2N \N H2 For the sake of brevity and convenience, the 1,4- dihydro form is employed'herein.

The term lower alkyl denotes a univalent saturated branched or straight hydrocarbon chain containing from 1 to 6 carbon atoms. Representative of such lower alkyl groups are thus methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. butyl, tert. butyl, pentyl, isopentyl, neopentyl, tert. pentyl, hexyl, and the like.

The term lower alkenyl denotes a univalent branched or straight hydrocarbon chain containing from 2 to 6 carbon atoms and nonterminal ethylenic unsaturation as, for example, vinyl, allyl, isopropenyl, 2-butenyl, 3-methyl-2-butenyl, Z-pentenyl, 3-pentenyl, Z-hexenyl, 4-hexenyl, and the like.

The term lower alkynyl denotes a univalent branched or straight hydrocarbon chain containing from 2 to 6 carbon atoms and nonterminal acetylenic unsaturation tially equimolar amounts when the amidine is reacted with the ylidenecyanoacetic acid whereas at least two molar equivalents of the amidine are employed per molar equivalent of the aldehyde reactant, in which case R and R are the same in the dihydropyridine product. The amidine reactant can be employed as the free base or in the form of a salt such as the hydrohalide salts with the amidine being liberated from the salt through treatment with a basic agent such as an alkali metal alkoxide.

It is rather surprising that the above described condensations produce the desired compounds in such good yields and with such high purity. Thus the water formed in the initial condensation of the aldehyde and amidine could be expected to hydrolyze the resultant ylideneamidine with formation of an lyideneamide. Moreover, while it is known that a benzylideneacetoacetic acid ester can be condensed with an amino crotonic acid ester to yield a l,4-dihydropyridine (Knoevenagel, Ber. 31, 743, i898), it would be expected from, for example, Silversmith, J. Org. Chem. 27, 4090 (1952) that the addition of the amidine to the ylideneamidine or the ylidenecyanoacetic acid would yield the dihydropyrimidine derivative rather than the dihydropyridine derivative.

Many of the aldehydes utilized as one of the reactants are known to the art and the others can either be generated in situ as herein described or prepared according to methods well known to the art, see for example Org. Reactions Vlll, 218 et seq. 1954). Typical of this reactant are the following compounds:

formaldehyde,

acetaldehyde,

propionaldehyde,

isobutyraldehyde,

cyclopentaldehyde,

cyclohexanaldehyde,

acrolein,

cyclohex-3-enaldehyde,

benzaldehyde,

2-, 3- and 4-methylbenzaldehyde,

2-, 3- and 4-methoxybenzaldehyde,

3,4 and 5-trimethoxybenzaldehyde,

2-isopropoxybenzaldehyde,

2-, 3- and 4-chlorobenzaldehyde,

2-, 3- 'and 4-bromobenzaldehyde,

2-, 3- and 4-fluorobenzaldehyde,

2,4- and 2,6-dichlorobenzaldehyde,

2,4- and 2,3-dimethylbenzaldehyde,

2-, 3- and 4-nitrobenzaldehyde,

2,6- and 3,5-dinitrobenzaldehyde,

2-nitro-6-bromobenzaldehyde,

2-nitro-3-methoxy-6-chlorobenzaldehyde, 2-nitro-4-chlorobenzaldehyde, 2-nitro-4-methoxybenzaldehyde,

2-, 3- and 4-trifluoromethylbenzaldehyde,

2-carbethoxybenzaldehyde,

3-carbomethoxybenzaldehyde,

4-carbobutoxybenzaldehyde,

3-nitro-4-carbethoxybenzaldehyde-4-carboxylic acid ethyl ester,

a,B- and y-pyridinaldehyde,

6-methylpyridin-Z-aldehyde,

pyrimidin-S-aldehyde,

4,6-dimethoxypyrimidin-5-aldehyde,

2-, 3- and 4-cyanobenzaldehyde,

2-methylmercaptobenzaldehyde, 4-methylmercaptobenzaldehyde, 2-methylsulphonylbenzaldehyde,

land Z-naphthaldehyde,

5-bromo-l-naphthaldehyde,

Z-ethoxy- 1 -naphthaldehyde,

4-methyll -naphthaldehyde,

quinolin-2-, 3-, 4-, 5-, 6-, 7- and 8-aldehyde,

isoquinolin-l ,3,4-aldehyde,

furan-Z-aldehyde,

thiophen-2-aldehyde and pyrrol-Z-alclehyde.

The ylidenecyanoacetic acid reactants are similarly known or can be readily produced according to known methods, see for example Newman et aL, J. Org. Chem, 23, 797 (1958). Typical of these reactants are the following benzylidenecyanoacetic acid methyl ester,

benzylidenecyanoacetic acid ethyl ester,

benzylidenecyanoacetic acid propargyl ester, benzylidenecyanoacetic acid B-methoxyethyl ester, l-naphthylidenecyanoacetic acid ethyl ester,

. Z-methoxybenzylidenecyanoacetic acid ethyl ester, 2-methylbenzylidenecyanoacetic acid ethyl ester, 2-nitrobenzylidenecyanoacetic acid isopropyl ester, 2-trifluoromethylbenzylidenecyanoacetic acid ethyl ester,

2-cyanobenzylidenecyanoacetic acid methyl ester,

2-chlorobenzylidenecyanoacetic acid propyl ester,

4-methylmercaptobenzylidenecyanoacetic acid ethyl ester,

a-pyridylmethylidenecyanoacetic acid ethyl ester, and

Z-furfurylidenecyanoacetic acid ethyl ester.

The amidine reactants are similarly known or can be readily produced according to known methods, see for example McElvain et all, J. A, C. S., 73. 2760 (1951). Typical of these reactants are the following:

amidinoacetic acid methyl ester,

amidinoacetic acid ethyl ester,

amidinoacetic acid n-propyl ester,

amidinoacetic acid isopropyl ester,

amidinoacetic acid cyclohexyl ester,

amidinoacetic acid B-methoxyethyl ester,

amidinoacetic acid a-ethoxyethyl ester,

amidinoacetic acid B-ethoxyethyl ester, amidinoacetic acid propargyl ester, amidinoacetamide, and amidino-N,N-dimethylacetamide.

As noted above, the compounds of the present invention demonstrate the ability to reduce blood pressure and to effect a dilation of the coronary vessels. They can accordingly be used where either or both of these effects are desired. Thus upon parenteral, oral or sublingual administration, the compounds produce a distinct and long lasting dilation of the coronary vessels which is intensified by a simultaneous nitrite-like effect of reducing the load on the heart, The effect on heart metabolism is thus one of energy saving. in addition, the compounds lower the blood pressure of normotonic and hypertonic animals and can thus be used as antihypertensive agents. These properties can be conveniently observed in well known laboratory models. Thus for example the coronary vessel dilation effect can be observed by measuring the increase in oxygen saturation in the coronary sinus in the narcotized, heart nitrophenyl 1,4- dihydropyridine3 ,5- dicarboxylic acid Continued l.\". Return to Dose A 7 normal Compound (mg/kg) saturation values (hours) 3,5-diethyl ester 2,6-diamino4-(3- 0,2 It I nitrophenyl l .4- dihydropyridine- 3.5-dicarboxylic acid diethyl ester The hypotensive activity of the present compounds can be observed by measuring the blood pressure of hy pertensive rats following administration of the compounds. The following table demonstrates the dose which results in at least a mm Hg reduction in blood pressure of such animals:

Compound Dose (mg/kg) 2,6-diamino-4(Z-methylphenyl l ,4- dihydropyridine-3,5dicarboxylic acid diethyl ester 2,6-diamino-4-( Z-nitrophenyl l ,4- dihydropyridine-3,S-dicarboxylic acid 3,5-diethyl ester 2,6 diamino-4( Z-methoxyphenyl )-l ,4- dihytlropyridine-S,S-dicarboxylic acid diethyl ester 2,6-diamino-4-( Z-cyanophenyl l ,4-dihydro 0.3 pyridine-3,5-dicarboxylic acid diethyl ester 2,6-diamino-4-( 3-nitrophenyl )-l ,4-dihydro- L0 pyridine-3,5 dicarboxylic acid diethyl ester In addition to the effect on blood pressure and coronary vessels, the compounds also lower the excitability of the stimulus formation and excitation conduction system within the heart so that an antifibrillation action is observed at therapeutic doses. The tone of the smooth muscle of the vessels is also greatly reduced. This vascularspasmolytic action can be observed in the entire vascular system as well as in more or less isolated and circumscribed vascular regions such as the central nervous system. In addition, a strong muscular spasmolytic action is manifested in the smooth muscle of the stomach, the intestinal tract, the urogenital tract and the respiratory system. Finally, there is some evidence that the compounds influence the cholesterol level and lipid level of the blood. These effects complement one another and the compounds are thus highly desirable as pharmaceutical agents to be used in the treatment of hypertension and conditions characterized by a constriction of the coronary blood vessels.

Pharmaceutical compositions for effecting such treatment will contain a major or minor amount, eg. from 95 to 0.5 percent, of at least one 2,6-diaminol ,4- dihydropyridine as herein defined in combination with a pharmaceutical carrier, the carrier comprising one or more solid, semi-solid or liquid diluent, filler and formulation adjuvant which is non-toxic, inert and pharmaceutically acceptable. Such pharmaceutical compositions are preferably in dosage unit form; i.e. physically discrete units containing a predetermined amount of the drug corresponding to a fraction or multiple of the dose which is calculated to produce the desired therapeutic response. The dosage units can contain one, two, three, four or more single doses or, alternatively, one-half, third or fourth ofa single dose. A single dose preferably contains, an amount sufficient to produce the desired therapeutic effect upon administration at one applicationofone or more dosage units according to a predetermined dosage regimen. usually a whole. half, third or quarter of the daily dosage administered once. twice, three or four times a day. Other therapeutic agents can also be present.

Although the dosage and dosage regimen must in each case be carefully adjusted, utilizing sound professional judgment and considering the age, weight and condition of the recipient, the route of administration and the nature and gravity of the illness, generally the daily dose will be from about 0.5 to about l800 mg/kg, preferably 2.5 to 900 mg/kg, when administered parenterally and from about 25 to about 4500 mg/kg, preferably 50 to 1800 mg/kg, when administered orally. In some instances a sufficient therapeutic effect can be obtained at lower doses while in others, larger doses will be required.

Oral administration can be effected utilizing solid and liquid dosage unit forms such as powders, tablets, dragees, capsules, granulates, suspensions, solution, and the like.

Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate as for example starch, lactose, sucrose, glucose or mannitol. Sweetening, flavoring, preservative, dispersing and coloring agents can also be present.

Capsules are made by preparing a powder mixture as described above and filling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.

Tablets are formulated for example by preparing a powder mixture, granulating or slugging, adding a labricant and disintegrant and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally with a binder such as carboxymethyl cellulose, an alginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate. The powder mixturecan be granulated by wetting with a binder such as syrup, starch paste, acacia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the resulting imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The medicaments can also be combined with free flowing inert carriers and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.

Oral fluids such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given quantity S rups can be prepared by dissolving the compound in a suitably flavored aqueous sucrose solution while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol esters. preservatives, flavor additives such as peppermint oil or saccharin, and the like can also be added.

Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax, or the like.

Parenteral administration can be effected utilizing liquid dosage unit forms such as sterile solutions and suspensions intended for subcutaneous. intramuscular or intravenous injection. These are prepared by sus pending or dissolving a measured amount of the compound in a non-toxic liquid vehicle suitable for injection such as an aqueous or oleaginous medium and sterilizing the suspension or solution. Alternatively a measured amount of the compound is placed in a .vial and the vial and its contents are sterilized and sealed. An

accompanying vial or vehicle can be provided for mixing prior to administration. Non-toxic salts and salt solutions can be added to render the injection isotonic. Stabilizers, preservatives and emulsifiers can also be added.

The following examples will serve to further typify the nature of the present invention through the presentation of specific embodiments. These examples should not be construed as a limitation on the scope of the invention since the subject matter regarded as the invention is set forth in the appended claims.

EXAMPLE 1 H,CZOOC COOCZH,

HZN g Na,

Upon boiling a solution of 5.3 g benzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for 2 hours, 2,6-diamin-4-phenyl-1,4- dihydropyridine-3,5-dicarboxylic acid diethyl ester of mp. 139C (isopropanol) is obtained.

Yield: 59 percent of theory.

EXAMPLEZ rgc ooc cooc a,

H N 2 NH.

. Upon boiling a solution of 7.6 g 2-n1trobenzaldehyde 8 dihydropyridine-3.5-dicarboxylic acid diethyl ester of mp. 142C (ethanol) is obtained.

Yield: 56 percent of theory.

EXAMPLE 3 Upon boiling a solution of 15.1 g 3- nitrobenzaldehyde and 26.0 g amidinoacetic acid ethyl ester in 250 ml ethanol for 2 hours, 2,6-diamino-4-(3- nitrophenyl)-1,4-dihydropyridine-3 ,5-dicarboxylic acid diethyl ester of m.p. 175-l7 6C (ethanol) is obtained.

Yield: 63 percent of theory.

cyanobenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in ml ethanol for 2 hours. 2.6-diamino- 4-(3-cyanophenyl)-1,4-dihydropyridine-3,5- dicarboxylic acid diethyl ester ofm.p. 176C (isopropanol) is obtained.

Yield: 55 percent of theory.

EXAMPLE 5 igc ooc l I COOCZH, H N 2; N55

Upon boiling a solution of 6.0 g 2- methylbenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for 2 hours, 2,6-diamin0- 4-(2-methylphenyl)-1,4-dihydropyridine-3 ,5-

dicarboxylic acid diethyl ester of mp. 158C (ethanol) is obtained.

Yield: 67 percent of theory.

EXAMPLE 6 Upon boiling a solution of 6.8 g 2 methoxybenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for 2 hours. lo-diamino- 4--(2-methoxyphenyl)-1.4-dihydropyridinc-3.5- dicarboxylic acid diethyl ester of mp. 147C (ethanol) is obtained.

Yield: 72 percent of theory.

fluorobenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for 1 hour, 2,6-diamino-4- (2-fluoropheny1)-1,4-dihydropyridine-3.S-dicarboxylic acid diethyl ester of m.p. 128130C (ethanol) is obtained.

Yield: 49 percent of theory.

EXAMPLE 8 2 00C ccoc a,

N HZN H Na Upon boiling a solution of 8.7 g Z-trifluoromethylbenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml of ethanol for 2 hours, 2,6-diamino-4-(2- trifluoromethylphenyl )-1 ,4-dihydropyridine-3,5- dicarboxylic acid diethyl ester of mp. 191C (ethanol) is obtained.

Yield: 70 percent of theory.

EXAMPLE9 rgc ooc cooc a,

H N 2 NH:

Upon heating a solution of 8.7 g 3-trifluoromethylbenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 m1 ethanol for 1 hour, 2,6-diamino-4-(3- trifluoromethylphenyl)-1,4-dihydropyridine-3 ,5- dicarboxylic acid diethyl ester of mp. 170C (isopropw n01) is obtained.

Yield: 56 percent of theory.

EXAMPLE a H, r-r,c,ooc I I cooc a, N

Upon boiling a solution of 5.0 g acctaldehydc and 261.11g amidinoacetic acid ethyl ester in 150 ml ethanol for 2 hours. 2.o-diamino-4-methyl-1.4- dihydropyridine-3.5-dicarboxylic acid diethyl ester of m.p. 136C (ethyl acetate/petroleum ether) is obtained.

Yield: 61 percent of theory.

EXAMPLE 1 1 Upon boiling a solution of 9.3 g 3-nitro-6- chlorobenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for 2 hours, 2,6-diamino- 4-(3-nitro-6-chlorophenyl)-1,4-dihydropyridine-3.5- dicarboxylic acid diethyl ester of mp. C (ethanol) is obtained.

Yield: 48 percent of theory.

EXAMPLE l2 Upon heating a solution of 5.4 g a-pyridinaldehyde and 13.0 g amidinoacetic acid ethyl ester in ml ethanol for 2 hours, 2,6-diamino-4-(a-pyridyl)-1,4- dihydropyridine-3,S-dicarboxylic acid diethyl ester of mp C (ethanol) is obtained.

Yield: 74 percent of theory.

EXAMPLE 13 can Upon heating a solution of 8.4 g 4,6- dimethoxypyrimidine-S-aldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for 2 hours. 2,6- diamino-4-(4,6-dimethoxypyrimid-5-y1)-l ,4- dihydropyridine-3,5-dicarboxylic acid diethyl ester of mp 219C (ethanol) is obtained.

Yield: 56 percent of theory.

EXAMPLE 14 a, 0 00c cooc a,

H2 N g rm Upon boiling a solution of 4.8 g furan-Z-aldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for 2 hours. 2.6-diamino-4-(furyl-2 )-l ,4- dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 147l48C (ethanol) is obtained.

Yield: 74 percent of theory.

EXAMPLE it, (1 000 0000 H,

H2 N 2 Nu Upon boiling a solution of 7.8 g l-naphthaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for 2 hours, 2,6-diamino-4-(naphth-l-yl)-l,4- dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. l62-l63C (ethanol) is obtained.

Yield: 52 percent of theory.

EXAMPLE l6 n,c,ooc I cooc n, Hm NH,

Upon heating a solution of 7.8 g quinoline-4- aldehyde and 13.0 g amidinoacetic acid ethyl ester in 200 ml ethanol for 2 hours, 2,6-diamino-4-(quinol-4- yl)-l,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 145 (ethanol) is obtained.

Yield: 58 percent of theory.

EXAMPLE l7 sca,

n, NH.

Upon heating a solution of 7.6 g 4-methylmercaptobenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 200 ml ethanol for 2 hours. 2,6-diamino-4-(4- methylmercaptophenyl)-1.4-dihydropyridine-3 ,5- dicarboxylic acid diethyl ester of m.p. 127C (isopropanol) is obtained.

Yield: 48 percent of theory.

EXAMPLE l8 Upon heating a solution of 9.1 g biphenyl-2aldehyde and 13.0 g amidinoacetic acid ethyl ester in 200 ml ethanol for 2 hours, 2,6-diamino-4-(biphenyl-2-yl)- l .4- dihydr0pyridine-3,S-dicarboxylic acid diethyl ester of m.p. 215 (ethanol) is obtained.

Yield: 33 percent of theory.

EXAMPLE 19 n nc c-cu ooc I I COOCHZCECII H n H NH:

Upon heating a solution of 7.6 g nitrobenzaldehyde and 14.0 g amidinoacetic acid propargyl ester in 200 ml ethanol for 2 hours, 2,6-diamino-4-(3-nitrophenyl)- 1,4-dihydropyridine-3,S-dicarboxylic acid dipropargyl ester of m.p. 170 (ethanol) is obtained.

Yield: 59 percent of theory.

EXAMPLE 20 iicoo coocatcn,

Upon heating a solution of 5.4 g pyridine-4-aldehyde and 14.4 g amidinoacetic acid isopropyl ester in 200 ml ethanol, 2,6-diamino-4-(pyrid-4-yl)-1,4- dihydropyridine3,5-dicarboxylic acid diisopropyl ester of m.p. 263C (ethanol) is obtained.

zylidenecyanoacetic acid ethyl ester. 7.2 g amidinoacetic acid isopropyl ester and 0.6 g sodium ethylate in ml ethanol for 4 hours, 2,6-diamino-4-phenyl-l ,4- dihydropyridine-3.S-dicarboxylic acid 3-ethyl ester 5- isopropyl ester of m.p. is obtained.

Yield: 54 percent of theory.

EXAMPLE 22 u '01 a 006 coocu(cn N "a" H AHZ Upon heating a solution of 12.3 g 2 nitrobenzylidenecyanoacetic acid ethyl ester. 7.2 g amidinoacetic acid isopropyl ester and 0.6 g sodium ethylate in 150 ml ethanol for 4 hours. 2.6-diamino-4- (Z-nitrophenyl l ,4-dihydropyridine-3 .S-dicarboxylic acid-3-isopropyl ester S-ethyl ester of m.p. 1 C is obtained.

Yield: 54 percent of theory.

azidobenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for 2 hours, 2,6-diamino-4-(2- azidophenyl l ,4-dihydropyridine-3 .S-dicarboxylic acid diethyl ester of m.p. 250C (ethanol) is obtained.

Yield: 46 percent of theory.

EXAMPLE 24 Upon boiling a solution of 8.9 g 3-carbethoxybenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 100 ml ethanol for 2 hours, 2,6-diamino-4-(3- carbethoxyphenyl)-1,4-dihydropyridine-3,5- dicarboxylic acid diethyl ester of m.p. 191C (ethanol) is obtained.

Yield: 32 percent of theory.

What is claimed is:

1. A process for the production of a compound of the formula wherein R is hydrogen; lower alkyl; alkenyl of 2 to 4 carbon atoms; alkynyl of 2 to 4 carbon atoms. phenyl; substituted phenyl in which the substituents are one to three members selected from the group consisting of lower alkyl, lower alkoxy, halogeno, nitro. cyano, trifluoromethyl, azido, carbo(lower alkoxy), lower alkylsulfonyl, lower alkylsulfinyl. and lower alkylthio; bi-phenyl; naphthyl; or a heterocyclic ring selected from the group consisting of quinolyl, isoquinolyl, pyridyl, pyrimidyl, thenyl, furyl and pyrryl, said heterocyclic ring being unsubstituted or substituted by one or two members selected from the group consisting of lower alkyl. lower alkoxy and halogeno; and

each of R and R taken independently of the other,

is lower alkoxy, lower alkoxy(lower alkoxy), alkenyloxy of 2 to 4 carbon atoms, alkynyloxy of 2 to 4 carbon atoms, amino, lower alkylamino or di(- lower alkyl)amino;

which comprises reacting an amidine of the formula or a salt thereof, wherein R is as above defined; with a. an aldehyde of the formula RCHO, wherein R is as above defined, in an inert organis colvent to produce a compound as above defined wherein R is the same as R or b. an ylidene cyanoacetic acid of the formula FCHR 1 I ll wherein R and R are as above defined; in an inert solvent and in the presence of an alkali metal alkoxide, the reaction temperature being from 20 to 200C, and recovering the compound produced.

2. A process according to claim 1 wherein R and R are lower alkoxy.

3. A process according to claim 2 wherein R is quinolyl, isoquinolyl, pyridyl, pyrimidyl, phenyl, furyl or pyr- Y ryl, unsubstituted or substituted by l or 2 members selected from the group consisting of lower alkyl, lower alkoxy and halogeno.

4. A process according to claim 2 wherein R is lower alkyl, naphthyl, phenyl, bi-phenyl, or phenyl substituted with from one to three substituents selected from the group consisting of lower alkyl, lower alkoxy. halogeno, nitro, cyano, trifluoromethyl, azido, carb(- lower alkoxy), lower alkylsulfonyl, lower alkylsulfinyl and lower alkylthio.

5. A process according to claim 1 wherein the alkali metal alkoxide is sodium methoxide.

6. A process according to claim 1 wherein the inert organic solvent is methanol, ethanol, propanol, dioxane, diethyl ether, glacial acetic acid, pyridine, di'methylformamide, dimethylsulphoxide or acetonitrile.

7. A process according to claim 1 wherein the reaction temperature is the boiling point of the solvent.

8. A process according to claim 1 wherein the reactants are employed in substantially equimolar amounts when the amidine is reacted with the ylidene cyanoacetic acid.

9. A process according to claim 1 wherein at least two molar equivalents of amidine are employed per molar equivalent of aldehyde reactant.

10. The process according to claim 1 wherein 2,6- diamino-4-phenyll .4-dihydropyridine-3.5- dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and benzaldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.

11. The process according to claim 1 wherein 2.6- diamino-4-( 2-nitrophenyl )-l ,4-dihydropyridine-3,5- dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and 2-nitrobenzaldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.

12. The process according to claim 1 wherein 2,6- diamino-4-( 3-nitrophenyl )-l ,4-dihydropyridine-3,5-

dicarboxylic acid diethyl ester is produced by reacting dicarboxylic acid diethyl ester is produced by reacting I amidinoacetic acid ethyl ester and 3- cyanobenzaldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.

14. The process according to claim 1 wherein 2,6- diamino-4-(2-methylphenyl)-1,4-dihydropyridine-3,5- dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and 2- methylbenzaldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.

15. The process according to claim 1 wherein 2,6- diamino-4-( Z-methoxyphenyl 1 ,4-dihydropyridine- 3,5-dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and 2- methoxybenzaldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.

16. The process according to claim 1 wherein 2,6- diamino-4-(2-fluorophenyl)-1,4-dihydropyridine-3,5- dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and 2- fluorobenzaldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.

18. The process according to claim 1 wherein 2,6-

diamino-4-( 3-trifluoromethylphenyl)-l ,4-

dihydropyridine-3,S-dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and 3-trifluoromethylbenzaldehyde in the presence of ethanol at the boiling point of'thc solution and recovering the compound produced.

19. The process according to claim 1 wherein 2.6- diamino-4-methyll ,4-dihydropyridine-3,5- dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and acetaldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.

20. The process according to claim 1 wherein 2,6- diamino-4-( 3-nitro-6-chlorophenyl l ,4- dihydropyridine-3,5-dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and 3-nitro-o-chlorobenzaldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.

21. The process according to claim 1 wherein 2,6- diamino-4-(a-pyridyl)-l ,4-dihydropyridine-3,5- dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and a-pyridinaldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.

22. The process according to claim 1 wherein 2,6- diamino-4-(4,6-dimethoxypyrimid-5-yl l ,4- dihydropyridine-3,S-dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and 4,o-dimethoxypyrimidine-S-aldehyde in the presence of ethanol at'the boiling point of the solution and recovering the compound produced.

23. The process according to claim 1 wherein 2.6- diamino-4-(furyl-2)-l ,4-dihydropyridine-3 ,5- dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and furan-Z-aldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.

24. The process according to claim 1 wherein 2,6- diamino-4-(naphth-l-yl)-1,4-dihydropyridine-3,5- dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and l-naphthaldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.

25. The process according to claim 1 wherein 2,6- diamino-4-(quinol-4-yl)- l ,4-dihydropyridine-3.5- dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and quinoline-4- aldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.

26. The process according to claim 1 wherein 2,6- diamino-4-( 4-methylmercaptophenyl )-l ,4- dihydropyridine-3,5-dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and 4-methylmercaptobenzaldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.

27. The process according to claim 1 wherein 2,6- diamino-4-(biphenyl-2-yl)-1,4-dihydropyridine-3,5- dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and biphenyl-Z-aldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.

28. The process according to claim 1 wherein 2,6- diamino-4-(3-nitrophenyl)-1 .4-dihydropyridine-3,5- dicarboxylic acid dipropargyl ester is produced by reacting amidinoacetic acid propargyl ester and nitrobenzaldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.

29. The process according to claim 1 wherein 2,6- diamino-4-( pyrid-4-yl l ,4-dihydropyridinc-3 .5- dicarboxylic acid diisopropyl ester is produced by reacting amidinoacetic acid isopropyl ester and pyridine 4-aldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.

30. The process according to claim 1 wherein 2,6- diamino-4-phei iyll ,4-dihydropyridine-3 .5- dicarboxylic acid 3-ethyl ester S-isopropyl ester is pro duced by reacting amidinoacetic acid isopropyl ester and benzylidenecyanoacetic acid ethyl ester in ethanol in the presence of sodium ethylate and recovering the compound produced.

31. The process according to claim 1 wherein 2,6- diamino-4-( Z-nitrophenyl )-l ,4-dihydropyridine-3,5- dicarboxylic acid-3-isopropyl ester S-ethyl ester is produced by reacting amidinoacetic acid isopropyl ester and 2-nitrobenzylidenecyanoacetic acid ethyl ester in ethanol in the presence of sodium ethylate and recovering the compound produced.

32. The process according to claim 1 wherein 2.6- diamino-4-( Z-azidophenyl l ,4-dihydropyridine-3,5- dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and 2- azidobenzaldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.

33. The process according to claim 1 wherein 2,6- diamino-4-( 3-carbethoxyphenyU-l ,4-dihydropyridine 3,5-dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and 3-carbethoxybenzaldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced. 

1. A PROCESS FOR THE PRODUCTION OF A COMPOUND OF THE FORMULA
 1. A process for the production of a compound of the formula
 2. A process according to claim 1 wherein R1 and R2 are lower alkoxy.
 3. A process according to claim 2 wherein R is quinolyl, isoquinolyl, pyridyl, pyrimidyl, phenyl, furyl or pyrryl, unsubstituted or substituted by 1 or 2 members selected from the group consisting of lower alkyl, lower alkoxy and halogeno.
 4. A process according to claim 2 wherein R is lower alkyl, naphthyl, phenyl, bi-phenyl, or phenyl substituted with from one to three substituents selected from the group consisting of lower alkyl, lower alkoxy, halogeno, nitro, cyano, trifluoromethyl, azido, carb(lower alkoxy), lower alkylsulfonyl, lower alkylsulfinyl and lower alkylthio.
 5. A process according to claim 1 wherein the alkali metal alkoxide is sodium methoxide.
 6. A process according to claim 1 wherein the inert organic solvent is methanol, ethanol, propanol, dioxane, diethyl ether, glacial acetic acid, pyridine, dimethylformamide, dimethylsulphoxide or acetonitrile.
 7. A process according to claim 1 wherein the reaction temperature is the boiling point of the solvent.
 8. A process according to claim 1 wherein the reactants are employed in substantially equimolar amounts when the amidine is reacted with the ylidene cyanoacetic acid.
 9. A process according to claim 1 wherein at least two molar equivalents of amidine are employed per molar equivalent of aldehyde reactant.
 10. The process according to claim 1 wherein 2,6-diamino-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and benzaldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.
 11. The process according to claim 1 wherein 2,6-diamino-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and 2-nitrobenzaldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.
 12. The process according to claim 1 wherein 2,6-diamino-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and 3-nitrobenzaldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.
 13. The process according to claim 1 wherein 2,6-diamino-4-(3-cyanophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and 3-cyanobenzaldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.
 14. The process according to claim 1 wherein 2,6-diamino-4-(2-methylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and 2-methylbenzaldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.
 15. The process according to claim 1 wherein 2,6-diamino-4-(2-methoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and 2-methoxybenzaldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.
 16. The process according to claim 1 wherein 2,6-diamino-4-(2-fluorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and 2-fluorobenzaldehyde in the presEnce of ethanol at the boiling point of the solution and recovering the compound produced.
 17. The process according to claim 1 wherein 2,6-diamino-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and 2-trifluoromethylbenzaldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.
 18. The process according to claim 1 wherein 2,6-diamino-4-(3-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and 3-trifluoromethylbenzaldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.
 19. The process according to claim 1 wherein 2,6-diamino-4-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and acetaldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.
 20. The process according to claim 1 wherein 2,6-diamino-4-(3-nitro-6-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and 3-nitro-6-chlorobenzaldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.
 21. The process according to claim 1 wherein 2,6-diamino-4-( Alpha -pyridyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and Alpha -pyridinaldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.
 22. The process according to claim 1 wherein 2,6-diamino-4-(4,6-dimethoxypyrimid-5-yl)-1,4-dihydropyridine-3,5 -dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and 4,6-dimethoxypyrimidine-5-aldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.
 23. The process according to claim 1 wherein 2,6-diamino-4-(furyl-2)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and furan-2-aldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.
 24. The process according to claim 1 wherein 2,6-diamino-4-(naphth-1-yl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and 1-naphthaldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.
 25. The process according to claim 1 wherein 2,6-diamino-4-(quinol-4-yl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and quinoline-4-aldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.
 26. The process according to claim 1 wherein 2,6-diamino-4-(4-methylmercaptophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and 4-methylmercaptobenzaldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.
 27. The process according to claim 1 wherein 2,6-diamino-4-(biphenyl-2-yl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and biphenyl-2-aldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.
 28. The process accordIng to claim 1 wherein 2,6-diamino-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid dipropargyl ester is produced by reacting amidinoacetic acid propargyl ester and nitrobenzaldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.
 29. The process according to claim 1 wherein 2,6-diamino-4-(pyrid-4-yl)-1,4-dihydropyridine-3,5-dicarboxylic acid diisopropyl ester is produced by reacting amidinoacetic acid isopropyl ester and pyridine-4-aldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced.
 30. The process according to claim 1 wherein 2,6-diamino-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester 5-isopropyl ester is produced by reacting amidinoacetic acid isopropyl ester and benzylidenecyanoacetic acid ethyl ester in ethanol in the presence of sodium ethylate and recovering the compound produced.
 31. The process according to claim 1 wherein 2,6-diamino-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-isopropyl ester 5-ethyl ester is produced by reacting amidinoacetic acid isopropyl ester and 2-nitrobenzylidenecyanoacetic acid ethyl ester in ethanol in the presence of sodium ethylate and recovering the compound produced.
 32. The process according to claim 1 wherein 2,6-diamino-4-(2-azidophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is produced by reacting amidinoacetic acid ethyl ester and 2-azidobenzaldehyde in the presence of ethanol at the boiling point of the solution and recovering the compound produced. 